A number of imidazopyrazine compounds are under investigation for inhibiting Spleen Tyrosine Kinase (Syk) activity. Syk is a non-receptor tyrosine kinase that plays critical roles in immunoreceptor- and integrin-mediated signaling in a variety of cell types, including B-cells, macrophages, monocytes, mast cells, eosinophils, basophils, neutrophils, dendritic cells, T-cells, natural killer cells, platelets, and osteoclasts.
Syk has been reported to play an important role in signaling through the B-cell receptor, known to be an important survival signal in B-cells. As such, inhibition of Syk activity may be useful for treating certain types of cancer, including B-cell lymphoma and leukemia. Additionally, the inhibition of Syk activity is believed to be useful for treating other diseases and conditions, including inflammatory diseases (e.g., rheumatoid arthritis), allergic disorders and autoimmune diseases.
One such compound that has been found to inhibit Syk activity is represented by Formula I:
or a pharmaceutically acceptable salt thereof. This compound and its synthesis have been described in U.S. Pat. Nos. 8,450,321 and 8,455,493, which are hereby incorporated herein by reference in their entirety, and are hereby incorporated by reference specifically with reference to Examples 1 and 2.
Early clinical programs have focused on oral administration of the compound of Formula I. What is desired is an oral formulation of the compound of Formula I that has low inter-subject variability, extended dose linearity, and low drug-drug-interaction. Additionally, what is desired is a commercially viable manufacturing process for the formulation of the compound of Formula I. For example, what is desired is a process that has little or no variability when different batches of the active pharmaceutical ingredient are produced, and that can be easily handled and manufactured on a commercial scale. What is also desired is a formulation that is both chemically and physically stable during the manufacturing process and upon storage.